WO2011113173A1

WO2011113173A1 - Cytarabine prodrug derivatives and use for resisting cancer or tumor thereof

Info

Publication number: WO2011113173A1
Application number: PCT/CN2010/000319
Authority: WO
Inventors: 高峰; 徐峻
Original assignee: Gao Feng; Xu Jun
Priority date: 2010-03-15
Filing date: 2010-03-15
Publication date: 2011-09-22

Abstract

The cytarabine prodrug derivatives of general formula (I), their synthetic routes, preparation and preparative method thereof, and use for resisting cancer or tumor. The derivatives are prepared by chemical modification on N4, O5 positions of cytarabine, which can avoid losing efficacy and inducing toxicity caused by N4-amino group metabolism, and make O5-hydroxy group be easily phosphorylated and activated. The derivatives can increase bioavailability, solubility and liposolubility, and reduce multidrug resistance.

Description

Description cytarabine derivatives and their use in anticancer and antitumor

The present invention relates to the field of medical technology, in particular to a novel cytarabine derivative and a synthetic route thereof, and to a cytarabine derivative preparation, a preparation method thereof and a cytarabine derivative and a preparation thereof Use in anti-cancer and anti-tumor. Background technique

Cancer is currently the most important disease that threatens human health. The existing methods of treating cancer include: surgical resection, radiotherapy, chemotherapy or the combination of these methods. Chemotherapy has been widely used and has been used in the treatment of many different types of cancer. However, most of the anticancer drugs used in chemotherapy are limited to delaying the deterioration of cancer and prolonging the life of the patient, making it difficult to achieve the goal of cure. Although the pathogenesis of various types of cancer varies, they are actually a large group of syndromes with common characteristics. In addition to the strong metabolism and constant differentiation of cancer cells, the physiological difference from normal cells is not very large. This is a huge challenge for developing drugs that selectively clear cancer cells without killing normal cells. Another major challenge in the development of anticancer drugs is cancer cell resistance, which is the drug resistance caused by a period of chemotherapy. The used chemotherapy drugs, even if increased dose, no longer play a role in cancer cells. Metastasis of tumor cells often also prevents treatment with chemotherapy. So far, no anticancer drug has been able to cure all cancers. Finding new, highly selective, low-toxic, non-resistant, and urgently needed new anti-cancer drugs remains challenging. Most chemotherapy and anticancer drugs can cause serious side effects, which can lead to the inability of chemotherapy to continue. Therefore, existing drugs are greatly limited in the treatment of different types of tumors. Therefore, the search for high-efficiency, low-toxic new anti-cancer drugs is still urgently needed to maintain human health.

Cytarabine is an analog of cytidine, an inhibitor of DNA polymerase. It can stop DNA synthesis, which can also incorporate DNA, interferes with DNA replication, and also blocks the reduction of cytosine nucleotides to deoxycytidine nucleotides (Sylvester, RK, Fisher, AJ, and Lobell, M., Drug Intelligence & Clinical Pharmacy: Vol. 21, No. 2, pp. 177-180 (1987); Boyer et al., Novel Cytarabine Monopho spate Prodrugs, United States Patent Application Publication, Pub. No. : US 2007/0037774 A 1 , ( Feb. 15, 2007); Colon-Cesario, M., Wang, J., Ramos, X., Garcia, HG, Davila, JJ, Laguna, J., Rosado, C, and Pena de Ortiz, S. , J Neurosci., 26(20): 5524 -5533 (2006).

Currently, cytarabine is mainly used for the treatment of acute leukemia. It is the best for acute myeloid leukemia. It is also effective for acute monocytic leukemia and acute lymphoblastic leukemia. It has certain curative effect on malignant lymphoma, lung cancer, digestive tract cancer, head and neck cancer. It has viral keratitis and epidemic. Conjunctivitis and the like also have a certain effect, however, it is ineffective for most solid tumors. The activity of cytarabine is not very high. In order to improve the therapeutic effect, cytarabine is generally combined with other drugs, such as: oxime daunorubicin, all-trans retinoic acid combined with arsenic trioxide, pirarubicin, topography Kang-Etoposide-cyclophosphamide, fludarabine and the like are used in combination. Cytarabine has side effects such as myelosuppression and digestive tract reaction. A few patients may have side effects such as abnormal liver function, fever, and rash (Bolwell, BJ, Cassileth, PA, Gale, . P. Leukemia. 2(5): 253- 60 (1988); Kimby, E., Nygren, P., Glimelius, B. Acta Oncol. 40(2-3): 231-22 (2001); Stamatopoulos, K. Leukemia Research, Volume 22, Issue 8 , pp 759 - 761, (2003); Burnett, AK, Milligan, D., Prentice, AG, Goldstone, AH, McMullin, MF, Hills, RK, Wheatley, K. Cancer. 109(6): 1007-10 (2007) ).

Cytarabine is an antimetabolite, which is catalyzed by deoxycytidine-catalyzed phosphorylation in cells, converted to active cytarabine, and further converted to the corresponding diphosphate and cytarabine. effect. Cytarabine inhibits DNA polymerase by interfering with the deoxycytidine triphosphate required for DNA synthesis, interfering with nucleotide incorporation into DNA, and inhibiting nucleotide reductase, preventing nucleotides from being converted into Deoxynucleotides, but have no significant effect on the synthesis of RNA and protein. They are cell cycle-specific drugs that act on S phase, and are most sensitive to the role of cells in S proliferative phase, and have a G1/S and S/G2 transition period. Also has a role. Immediately disappeared from the blood after intravenous injection, 40% passed The blood-brain barrier, the drug is mainly metabolized in the liver to inactive uridine, 70% ~ 90% through the kidney. In order to develop new anticancer drugs that are effective against solid tumors such as liver cancer, new drugs for liver targeting must be sought. Obviously, anti-hepatitis drugs can be an excellent reference. For example, miftine and adefovir (PMEA) have been approved as anti-viral therapeutics for hepatitis B (Starrett, et al""Synthesis, oral bioavailability determination, and in vitro evaluation of prodrugs of the antiviral agent 9 -[2-(phosphonomethoxy)ethyl]adenine (PMEA)," J Med Chem., 37(12): 1857-64 (1994); Shaw, et al""Pharmacokinextics and Metabolism of Selected Prodrugs of PMEA in Rats," Drug Metabolism Dis., 25(3): 362-366 (1997); Wacher, VJ, et al., Advanced Drug Delivery Reviews 46:89-102 (2001); Wacher, et al""Active Secretion and Enterocytic Drug Metabolism Barriers to Drug Absorption," Adv. Drug Del. Rev., 46:89-102 (2001); Murono, et al., "Prevention and inhibition of nasopharyngeal carcinoma growth by antiviral phosphonated nucleoside analogs," Cancer Res., 61 ( 21): 7875-7 (2001). In 2003, scientists of Metabasis Therapeutics, Inc. K. Raja Reddy, Mark D. Erion, Michael C. Matelich, Joseph J. Kopcho proposed the use of cyclic citrate nucleosides as anti-hepatocellular carcinoma Prodrug for therapeutic drugs (U Nited States Patent 7,214,668;), when the compound enters the liver, it is catalyzed by the liver's CYP 3A4 metabolizing enzyme to form an acyclic nucleoside derivative and has anticancer activity. In 2007, Metabasis Therapeutics, Inc. proposed another new Patent application of cyclic cytarabine cytarabine derivatives as anticancer prodrugs (Novel Cytarabine Monopho spate Prodrugs, United States Patent Application Publication, Pub. No.: US 2007/0037774 A 1, Boyer et al" Feb. 15, 2007; Phosphonic acid based prodrugs of PMEA and its analogues, United States Patent 7,214,668, Reddy, et al. May 8, 2007). The core of these patent applications is the attachment of cyclic phosphate to the -OCH2-ribose position on the ribose ring of cytarabine, the O5 position, without modification of the amino group on the cytosine cytosine ring.

Cytarabine (see Figure 1) is generally not used to treat liver cancer because its nucleoside backbone structure is metabolically inactivated and causes toxicity when its nucleoside backbone structure enters the liver; The O5 hydroxyl group must be activated by phosphorylation, and this activation process is too much in the liver. Slow. Summary of the invention

The present invention aims to overcome the deficiencies of the prior art mentioned above, and to provide a cytarabine derivative which is highly efficient, low toxicity, non-resistance, can be rapidly activated, and provides a synthetic route of cytarabine derivatives and The method for preparing a cytarabine derivative preparation, and the present invention also provides experimental data for the use of a cytarabine derivative and a preparation thereof for anticancer and antitumor.

The cytarabine derivative of the present invention, characterized in that the cytarabine derivative is a compound having the following formula I:

Formula I

Wherein, when X = OH, W represents any one of C=O, S(O)O and C(O)O; and Z is an alkyl group or any of the following representative groups:

Wherein, m = 0, l, 2; n = 1, 2, 3; the n-indicating group contained in the parenthesis indicated by the n may be substituted to the benzene ring, the aromatic ring, the naphthalene ring, the carbocyclic ring, the heterocyclic ring Any one of o-, m-, p- or any of i ^:, i-, 3-- or any one of α- and β-f or a combination of these positions; Wherein R ¹ R ² is (^ _-18 saturated or unsaturated aliphatic group, the unsaturated aliphatic group contains one or more unsaturated bonds, and the unsaturated bond includes cis or trans And R ³ is an alkyl group selected from the group consisting of H, OH, OCOR, ester group COOR, dC ₁₈ alkyl group, C _{3 - 18} cycloalkyl group, C ₂ _ ₁₀ alkenyl group, alkynyl group, Trifluoromethyl, benzyl, phenyl, aryl, halo, acyl, carbonyl, cyano, amino, substituted amino, nitro, xanyl, amide, CONR, ₂ and NHCOR', Any one of a yellow amide group, an amino acid, a carbocyclic group, a heterocyclic group, an alkoxy group, and an alkylthio group SR; wherein R is an RR ² as defined above; wherein X≠OH When X is O-PCOXOR ¹ ^ or phosphate group or

Wherein A represents any of O, S and CH ₂ , p = l-5, and the phosphate group includes a monophosphate group, a diphosphate group and a triphosphate group, and WZ represents a hydrogen atom or W and Z respectively represent A group as defined above.

The above R ^1, R ² may be H, C _1-18 alkyl, a C _3-18 cycloalkyl, C _2-18 alkenyl, C _2-18 alkynyl group, and. Any one of a cycloalkenyl group, a benzyl group, a phenyl group, an aromatic ring group, a carbocyclic group and a heterocyclic group. Each of these groups may be further substituted, and may contain a hetero atom therein.

For the sake of clarity, but not limitation of the invention, all technical and scientific terms used in the present invention have the same meaning as commonly used and understood by the skilled artisan in the field of the invention. The patent applications or published applications and other papers cited in the present invention are the original references and are not modified.

As used herein, "a" or "an" or "a" or "an"

As used herein, "alkyl" means various saturated straight-chain, side-chain or cyclic hydrocarbon groups, particularly including small alkyl groups having ten or ten carbons or less. For example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, heptyl, octyl and decyl Some typical examples in this definition.

The "alkenyl group" used in the present invention has the same meaning as the above "alkyl group", but it must have at least one carbon-carbon double bond (C=C), so the alkenyl group used in the present invention includes a straight line containing two to ten carbon atoms. Chain a hydrocarbon group having a branched or cyclic group and having at least one carbon-carbon double bond, such as a vinyl group, a propenyl group, a butenyl group, a pentenyl group, and the like.

The "alkynyl group" used in the present invention is the above alkyl group or alkenyl group and contains at least one carbon-carbon triple bond (C≡ C ). Therefore, the alkynyl group includes two to ten carbon atoms and contains at least one carbon-carbon triple bond. Linear, branched or cyclic hydrocarbyl or alkynyl groups such as ethynyl, propynyl, butynyl and pentynyl.

"Saturated" in the present invention means that the group does not contain an unsaturated bond, such as a carbon-carbon double bond or a carbon-carbon triple bond; and "unsaturated" means that the group contains one or more carbon-carbon doubles. Key or carbon-carbon triple bond.

The "cycloalkyl group" used in the present invention is a cyclic hydrocarbon group and preferably a cycloalkyl group having three to eight carbons. Thus cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane and cyclooctane are typical examples of this definition. The cycloalkyl group contains one or two carbon-carbon double bonds to form a "cycloalkenyl group". The cycloalkyl group may also carry an alkyl group, an alkenyl group, an alkynyl group and other groups.

The "aromatic group" used in the present invention is a cyclic conjugated aromatic system and may contain one or more non-carbon atoms (other than carbon other nitrogen such as nitrogen) such as phenyl, naphthyl and pyridine in the ring. Base.

The "heterocyclic group" which is also commonly used in the present invention means a cyclic group and a compound in which a plurality of atoms are constituted by a covalent bond, and which contains at least one non-carbon atom. Specifically, the heterocyclic group includes a five- and six-membered ring system containing a non-carbon atom such as nitrogen, sulfur or oxygen such as pyrazole, pyrrole, pyridine or pyrimidine.

The "alkoxy group" in the present invention means an alkyl group which is formed by linking an oxygen atom to a linear or branched alkyl group. Examples of such alkoxy groups include methoxy, ethoxy, propoxy or isopropoxy groups and the like.

Similarly, "alkylthio" refers to an alkylsulfide group formed by linking a sulfur atom to a linear or branched alkyl group. Examples of such alkylthio groups include sulfonylthio, ethylthio, propylthio or isopropylthio and the like.

The "halogen atom group" in the present invention is fluorine, chlorine, bromine or iodine.

"Amino acid" in the present invention refers to a substituted natural and non-natural amino acid, a pure L- or D-configuration or a racemic mixture, and a group derived from an amino group and a carboxyl group. It is particularly worthy of further elaboration that the various substituents defined above also include groups which are further substituted, wherein these new substituents may also contain other groups. For example, a hydrogen atom on an alkyl group or an aromatic group is substituted with an amino group, a phenol or another group to become a new group belonging to each of the above definitions.

The "phosphoric acid" or "phosphate ester" used in the present invention is the highest oxidation state of the pentavalent phosphorus atom to which four oxygen atoms are attached, one oxygen atom is bonded to the phosphorus atom by a double bond, and the two oxygen atoms are bonded to the phosphorus atom by a single bond. The atoms are connected, and the two oxygen atoms may be hydrogen atoms, negative charges or various alkyl groups, aromatic groups, etc. as defined above, such as -P(=O)(O-) ₂ , -P(O) (OR) ₂ . Another oxygen atom on the phosphorus atom is attached to the derivative of the present invention.

The "prodrug" in the present invention means a compound which cleaves or increases the biological action formed by a certain structural unit in the body after the cytarabine derivative of the present invention is used in the body.

The structural formula of the representative cytarabine derivative of the present invention is as follows:

The organic solvents mentioned in the present invention include: hexaphosphoric acid benzotriazolyloxytripyrrole phosphorus (PyBOP) 4-dimethylaminopyridine (DMAP) hydrazine, hydrazine-dimethylformamide (DMF) Dimercaptosulfoxide (DMSO), polyethylene glycol (PEG) and tetrahydrofuran (THF) Another technical problem solved by the present invention is to provide a simple and effective synthetic route for a plurality of cytarabine derivatives of the general formula (I), the technical solutions of which are as follows:

1. A synthetic route of cytarabine derivatives, characterized in that: cytarabine and acetic anhydride are dissolved in decyl alcohol, and the reaction mixture is heated under reflux for 4 hours, and the obtained reaction solution is purified by column chromatography column to obtain a pass. A cytarabine derivative of formula (I). (Refer to synthetic route 1)

2. A synthetic route of cytarabine derivatives, characterized in that: cytarabine, acetylsalicylic acid or o-decyloxybenzoic acid, PyBOP and DMAP are dissolved in DMF, stirred at room temperature for 12 hours to obtain a reaction solution, The reaction liquid is purified by column chromatography or the reaction liquid is suspended with water, washed with ethyl acetate, and the aqueous layer is allowed to stand to precipitate crystals, which are filtered and dried to obtain a cytarabine derivative of the formula (I). (Refer to synthetic route 2, 3)

3. The synthetic route of cytarabine derivatives, including the following steps:

(1) The phthalic anhydride or dianhydride compound is mixed with a fatty alcohol, heated and melted, reacted for 4 to 5 hours, and cooled to obtain the first intermediate product (A), which is directly used in the next reaction without further purification; (2) The cytarabine, the first intermediate product (A), PyBOP and DMAP are dissolved in DMF, stirred at 25-50 ° C for 12 24 hours, and the obtained reaction solution is purified by column chromatography or by reaction. The liquid is poured into water, and the solid is precipitated. The obtained solid is purified by column chromatography or the obtained reaction liquid is poured into water, and extracted with ethyl acetate three times. The ethyl acetate solution is dried over anhydrous sodium sulfate, filtered, filtered, liquid The mixture was evaporated to dryness under reduced pressure to give a cytidine derivative of the formula (I). (Refer to Schemes 4 to 14) The fatty alcohol is any one of decyl alcohol, n-butanol, lauryl alcohol, n-tetradecyl alcohol, n-hexadecanol and n-octadecanol.

4. The synthetic route of cytarabine derivatives, including the following steps:

(1) The fatty alcohol is dissolved in tetrahydrofuran or dioxane, then 1,4-cyclohexanedicarboxylic acid and p-toluenesulfonic acid are added, and the mixture is heated under reflux for 5 hours to obtain a second intermediate product (B) which is not further purified. , used directly in the next reaction;

(2) Dissolving cytarabine, second intermediate product (B), PyBOP and DMAP in DMF, stirring at room temperature for 12 hours, pouring the reaction solution into water to precipitate a solid, and then extracting the solid by column chromatography The cytarabine derivative of the formula (I) is obtained purely. (Refer to Schemes 15 to 19) The fatty alcohol is any one of n-decyl alcohol, lauryl alcohol, n-tetradecyl alcohol, n-hexadecanol and n-octadecanol.

5. The synthetic route of cytarabine derivatives, including the following steps:

(1) Adding isophthalic acid or phthalic acid to SOCl ₂ , adding DMF, heating under reflux, reacting for 4 hours, and spinning off SOCl ₂ to obtain a third intermediate product (C) without further purification. , used directly in the next reaction;

(2) The fatty alcohol is dissolved in dioxane and then added to Et ₃ N, and the third intermediate (C) is dissolved with dioxane. The fatty alcohol was added dropwise to the third intermediate product C under an ice bath, and the reaction was carried out for 4 hours, and the solvent was distilled off to obtain a fourth intermediate product (D);

(3) Dissolving cytarabine, fourth intermediate product (D), PyBOP and DMAP in DMF, stirring at room temperature for 12 hours, and separating and purifying the reaction solution to obtain cytarabine^"bio. Synthetic route 20~29)

The fatty alcohol is any one of n-decyl alcohol, lauryl alcohol, n-tetradecyl alcohol, n-hexadecanol and n-octadecanol.

6. The synthetic route of cytarabine derivatives, including the following steps:

(1) P0C1 _{3 was} dissolved in triethyl phosphate at 0 °C, and cytarabine was added for 1 h. The reaction mixture was washed with diethyl ether to obtain a fifth intermediate (E), which was used in the next step without purification. ;

(2) The fifth intermediate product (E) is added to the fatty alcohol, stirred at 60-80 ° C for 4-5 h, diluted with hydrochloric acid to adjust the pH to 7, and the dry fatty alcohol is rotated to obtain the general formula (I). Cytosine derivatives. (Refer to synthetic route 30~33)

The fatty alcohol is any one of decyl alcohol, absolute ethanol, n-butanol, and n-octanol.

The preparation method of the cytarabine derivative preparation of the invention comprises the following steps:

(1) The cytarabine derivative of the formula (I) is dissolved in water, physiological saline, aqueous cyclodextrin solution, water-soluble organic solvent, nonionic surfactant, water-soluble lipid, fatty acid, fat Preparing a formulation solution by combining a solvent of any one or more of an acid ester and a phospholipid; (2) The preparation solution is further diluted with physiological saline or glucose injection to prepare a cytarabine derivative preparation.

The organic solvent refers to a combined solvent of one or more of ethanol, propylene glycol, glycerin, glycerin, polyethylene glycol, hydrazine, fluorenyl-dimercaptoamide, and dimethyl sulfoxide.

The cytarabine derivative preparation of the present invention is characterized in that it is a product prepared by the above-described method for producing a cytarabine derivative preparation.

Use of the cytarabine derivative of the invention for anticancer and antitumor. The cytarabine derivative of the formula (I) can be used to treat or alleviate cancer in a certain tissue or organ. Cancer includes, but is not limited to, leukemia, solid tumors, lung cancer, colon cancer, liver cancer, central nervous system tumors, ovarian cancer, and kidney cancer.

The present invention provides the use of an cytarabine derivative preparation comprising an effective dose of a cytarabine derivative of the formula I in antitumor chemotherapy and the combination of the cytarabine derivative preparation with other chemotherapeutic agents, Use in anti-tumor chemotherapy. The cancer includes leukemia, solid tumor, lung cancer, colon cancer, liver cancer, central nervous system tumor, ovarian cancer, and kidney cancer. Antitumor drugs which can be used in combination with the preparation of the cytarabine derivative of the present invention include, but are not limited to, alkylating agents, plant alkaloids, antibacterial antitumor sulfonamides, platinum drugs, antimetabolites and others. Known anticancer drugs. The combination therapy referred to in the present invention includes the use of at least one cytarabine derivative exemplified in the present invention.

The pharmaceutical preparation is prepared by using the cytarabine derivative of the formula I of the present invention as a component, and can be administered orally or parenterally. The parenteral administration referred to herein means subcutaneous, intravascular, intraarterial, intrauterine, intraatrial, intrasynovial, intrasternal injection or instillation.

The present invention contemplates the design of cytarabine derivatives using new design techniques. Cytarabine (see Figure 1) cannot be used to treat liver cancer. On the one hand, when its nucleoside skeleton structure enters the liver, its Ν4 amino group is metabolically inactivated and causes toxicity, and on the other hand, its glycocalyx structure The upper 05 hydroxyl group must be activated by phosphorylation, and this activation process is too slow in the liver.

The cytarabine derivative of the present invention is designed by chemically modifying the position of Ν4, 05 to design a novel prodrug derivative, thereby avoiding metabolic failure of Ν4 amino group and causing toxicity; The 05 hydroxyl group is easily activated by phosphorylation, and the main beneficial effects are: increased bioavailability, reduced multi-drug resistance (multi-target design technique), increased solubility, and increased ester solubility. The invention provides a synthetic route of cytarabine derivatives, a cytarabine derivative preparation and a preparation method thereof, and proves that the cytarabine derivative of the invention has anticancer and antitumor effects through a large amount of experimental data. the use of. DRAWINGS

Figure 1 is a schematic diagram showing the structure of cytarabine and the position of modification of N4, 05.

Fig. 2 is a view showing the structure of a representative cytarabine derivative which modifies the N4 position of cytarabine of the present invention.

Fig. 3 is a view showing the structure of a representative cytarabine derivative which modifies the position of cytarabine 05 of the present invention.

Fig. 4 is a graph showing the representative drug concentration-inhibition rate of the cytarabine derivative of the present invention inhibiting the BEL-7402 liver cancer cell line. detailed description

The synthetic routes of some representative cytarabine derivatives of the present invention are listed below. Other similar cytarabine derivatives of the invention are synthesized by the same or similar methods. Synthetic route 1 :

Synthesis of cytarabine derivative 1 (Scheme 1): Cytarabine (1.0 g, 4 mmol) and acetic anhydride (0.9 ml, 4.8 mmol) were dissolved in sterol MeOH (500 ml). The reaction mixture is heated back Stream for 4 hours. The reaction solution was purified by column chromatography (silica gel, solvent: dichloromethane / decyl alcohol = 10/1) to give cytidine derivative 1 (84.6 mg), LC (UV 254 nm) purity >95 % LC-MS m/z 286 [M + H] (Molecular formula C _u H ₁₅ N ₃ O ₆ , molecular weight 285 ) 1H NM ( 600 MHz, DMSO-d ₆ ) δ 10.84 ( s, 1H ) , 8.06 (d, 1H) , 7.18 ( d, 1H ) , 6.05 ( d, 1H) 5.50 ( d 1H) 5.49(d, 1H), 5.06 ( t 1H ) 4.06 (m 1H) 3.94 (m, 1H) , 3.83 ( m, 1H ), 3.61 ( t, 2H ) , 2.10 ( t, 3H ) Synthetic route 2:

Synthesis of cytarabine derivative 2 (Route 2): cytarabine ( 1.21 g, 5 mmol), acetyl 7 salicylic acid (1.08 g, 6 mmol) PyBOP (2.6 g, 5 mmol) and DMAP (0.1 g , 0.5 mmol) dissolved in DMF (20 ml). The reaction solution was stirred at room temperature for 12 hours. The reaction solution was purified by column chromatography (silica gel, solvent: methylene chloride / methanol = 20/1) to give cytidine derivative 2 ( 16.7 mg ) , LC (UV 254 nm ) purity >90% LC — MS m/z 364 [M + H] (Molecular formula C ₁₇ H ₁₉ N ₃ 0 ₈ , molecular weight 363 ) „ 3⁄4 NMR (600 MHz, DMSO-^) 5 11.83 ( s, 1H) , 10.94 ( s, 1H) , 8.15 ( t, 1H ) 7.97 ( d, 1H ) , 7.48 ( s, 1H ) , 7.40 ( t 1H ) 7.06 ( m 1H) 7.00 ( s 1H ) 6.07 ( d, 1H ) 5.54 ( s, 1H) , 5.50 ( d, 1H) , 5.10 ( t, 1H) , 4.09 ( m, 1H) , 3.94 ( m, 1H) , 3.84 (m 1H) , 3.63 ( t, 2H ) Synthetic route 3:

Synthesis of cytarabine derivative 3 (Scheme 3): cytarabine (1.2 g, 5 mmol), o-decyloxybenzoic acid (0.8 g, 5 mmol). PyBOP (2.6 g, 5 mmol) and DMAP (0.1 g, 0.5 mmol) was dissolved in DMF (20 mL). The reaction solution was suspended with water, washed with ethyl acetate, and the aqueous layer was allowed to stand, crystals were precipitated, filtered, and dried to obtain cytidine derivative 3 (69 mg). The purity of LC (UV 254 nm) was 98%. LC-MS m/z 378 [M + H] ⁺ (Molecular formula C ₁₇ H ₁₉ N ₃ O ₈ , molecular weight 377 ). Synthetic route 4:

Synthesis of the first intermediate product A4 (Scheme 4): The dianhydride compound (1.5 g, 10 mmol) was dissolved in CH ₃ OH (20 ml) and heated to reflux for 4 hours. The CH ₃ OH was distilled off under reduced pressure to give the crude intermediate product A4 directly to the next reaction. Synthesis of cytarabine derivative 4 (Scheme 4): cytarabine (2.5 g, 10 mmol), first intermediate Α4 (2.0 g, 10 mmol), PyBOP (5.2 g, 10 mmol) and DMAP ( 0.2 g, 2 mmol) was dissolved in DMF (10 ml) and stirred at room temperature for 12 h. The reaction solution was purified by column chromatography (silica gel, solvent: methylene chloride/methanol = 10/1) to give cytidine derivative 4 (p. isomer, 51.8 mg), LC (UV 254) Nm) purity 96%. LC-MS m/z 412 [M + H] + (Molecular formula C ₁₈ H ₂₅ N ₃ O ₈ , molecular weight 411 ). Synthetic route 5:

Synthesis of the first intermediate product A5 (Scheme 5): The dianhydride compound (1.5 g, 10 mmol) was dissolved in n-butanol (20 ml) and heated to reflux for 4 hours. The n-butanol was distilled off under reduced pressure to obtain the first intermediate product A5 of the crude product which was directly used for the next reaction.

Synthesis of cytarabine derivative 5 (Scheme 5): cytarabine (2.5 g, 10 mmol), first intermediate Α5 (2.2 g, 10 mmol), PyBOP (5.2 g, 10 mmol) and DMAP (0.2 g, 2 mmol) Dissolved in DMF (10 ml) and stirred at room temperature for 12 h. The reaction solution was purified by column chromatography (i.p. silica gel, solvent: dichloromethane / decyl alcohol = 20/1) to give cytidine derivative 5 (-p-isomer, 49.4 mg), LC ( UV 254 nm) purity 98%. LC-MS m/z 476 [M + Na] s (M. C ₂₁ H ₃₁ N ₃ O _s , molecular weight 453). Synthetic route 6:

Synthesis of the first intermediate product A6 (Scheme 6): Diacid liver compound (3.08 g, 20 mmol) and lauryl alcohol (4.46 g, 24 ml) were dissolved in tetrahydrofuran (20 ml) at a temperature of 50. C, reaction 4 hours. The obtained first intermediate A6 was used in the next step without further purification.

Synthesis of cytarabine derivative 6 (Scheme 6): cytarabine (1 g, 4.1 mmol), first intermediate Α6 (1.53 g, 4.5 mmol), PyBOP ( 2.35 g, 4.5 mmol) and DMAP ( 0.055 g, 0.41 mmol) dissolved in DMF (10 mL). The reaction solution was poured into water, and a solid was precipitated. The solid was filtered, and purified by column chromatography chromatography (silica gel, solvent: methylene chloride / decyl alcohol = 15/1) to obtain cytarabine derivative 6 (42.4 Mg ), LC (UV 254 nm ) purity >95%. LC-MS m/z 564 [M + H] ⁺ (Molecular formula C ₂₉ H ₄₇ N ₃ O ₈ , molecular weight 565 ). Synthetic route 7:

Synthesis of the first intermediate product A7 (Scheme 7): phthalic anhydride (14.8 g, 100 mmol) was dissolved in 30 ml of butanol, and then reacted at 70 ° C for 5 hours, and the filtrate was evaporated to dryness to give a first intermediate product. A7 was used directly in the next step without further purification.

Synthesis of cytarabine derivative 7 (Scheme 7): cytarabine (2.43 g, 10 mmol), first intermediate Α7 (2.22 g, 10 mmol), PyBOP (5.7 g, 11 mmol) It was dissolved in DMF (10 ml) with DMAP (0.12 g, 1 mmol) and stirred at room temperature for 24 hours. The reaction solution was purified by column chromatography (silica gel, solvent: dichloromethane / decyl alcohol = 10/1) to give cytidine derivative 7 (251.9 mg), LC (UV 254 匪) purity > 95% ). LC-MS m/z 448 [M + H] dec. (M. C ₂₁ H ₂₅ N ₃ 0 ₈ , molecular weight 447). Synthetic route 8:

Synthesis of the first intermediate product A8 (Scheme 8): The dianhydride compound (3.0 g, 19.5 mmol) was mixed with n-tetradecanol (4.2 g, 19.6 mmol), heated and melted, reacted for 4 hours, and cooled to give a colorless oil. The liquid first intermediate A8 was used directly in the next reaction without further purification. Synthesis of cytarabine derivative 8 (route): cytarabine (1 g, 4.1 mmol), first intermediate A8 (1.7 g, 4.5 mmol), PyBOP ( 2.35 g, 4.5 mmol), and DMAP ( 0.055 g, 0.45 mmol) Dissolved in DMF (10 ml), stirred at 50 °C for 12 hours. The reaction solution was poured into water to precipitate a solid. The solid was purified by column chromatography (silica gel, solvent: methylene chloride / Sterol = 15/1) to obtain cytarabine derivative 8 (78.7 mg). LC (UV 254 nm) purity 97%. LC-MS m/z 594 [M + H] ⁺ (Molecular formula C ₃₁ H ₅₁ N ₃ O ₈ , molecular weight 593 ).

Synthesis of the first intermediate product A9 (Scheme 9): The dianhydride compound (3.0 g, 19.5 mmol) was mixed with n-hexadecanol (4.7 g, 19.4 mmol), heated and melted, reacted for 4 hours, and cooled to give a colorless oil. The liquid first intermediate A9 was used directly in the next reaction without further purification. Synthesis of cytarabine derivative 9 (Scheme 9) 1 Cytarabine (1 g, 4.1 mmol), first intermediate Α9 (1.8 g, 4.5 mmol), PyBOP ( 2.35 g, 4.5 mmol), and DMAP (0.055 g, 0.45 mmol) Dissolved in DMF (10 ml) and stirred at 50 °C for 12 h. The reaction solution was poured into water to precipitate a solid, which was then purified by column chromatography (silica gel, solvent: methylene chloride / decyl alcohol = 15/1) to obtain cytarabine derivative 9 (103.2 mg). LC (UV 254 nm) purity 95%. LC-MS m 622 [M + H] ⁺ (M. C ₃₃ H ₅₅ N ₃ O ₈ , molecular weight 621 ).

Synthesis of the first intermediate product A10 (Scheme 10): The dianhydride compound (3.0 g, 19.5 mmol) was mixed with n-octadecyl alcohol (5.3 g, 19.6 mmol), heated and melted, reacted for 4 hours, and cooled to give a white solid. An intermediate product A10 was used in the next step without further purification.

Synthesis of cytarabine derivative 10 (Scheme 10): cytarabine (1 g, 4.1 mmol), first intermediate A10 (1.9 g, 4.5 mmol), PyBOP ( 2.35 g, 4.5 mmol), and DMAP (0.055 g, 0.45 mmol) Dissolved in DMF (10 ml) and stirred at 35 °C for 12 h. The reaction solution was poured into water to precipitate a solid, and the solid was purified by column chromatography (silica gel, solvent: methylene chloride / decyl alcohol = 15/1) to obtain cytarabine derivative 10 (79.3 mg). LC (UV 254 nm) purity 96%. LC-MS m/z 672 [M + Na] ⁺ (M. C ₃₅ H ₅₉ N ₃ O ₈ , molecular weight 649).

Synthesis of the first intermediate product All (Scheme 11): phthalic anhydride (5 g, 34 mmol) was mixed with lauryl alcohol (7.5 g, 40 mmol), heated and melted, reacted for 4 hours, cooled, and whitened. The first intermediate of the solid, All, was used directly in the next reaction without further purification. Synthesis of cytarabine derivative 11 (Scheme 11): cytarabine (lg, 4.1 mmol), first intermediate All (2.2 g, 5 mmol), PyBOP ( 2.35 g, 4.5 mmol) and DMAP (0.055 g, 0.45 mmol) was dissolved in DMF (10 ml) and stirred at room temperature for 12 h. The reaction mixture was poured into water to precipitate a solid, and the solid was purified by column chromatography (silica gel, solvent: methylene chloride/methanol = 15/1) to give cytidine derivative 11 (124.3 mg). LC (UV 254 nm) purity 98%. LC-MS m 582 [M + Na] ⁺ (Molecular formula C ₂₉ H ₄₁ N ₃ O ₈ , molecular weight 559 ).

Synthesis of the first intermediate product A12 (Scheme 12): Phthalic anhydride (3.0 g, 20 mmol) was mixed with n-tetradecanol (4.8 g, 22 mmol), reacted at 80 ° C for 5 hours, cooled, and whitened. The solid first intermediate A12 was used directly in the next reaction without further purification. Synthesis of cytarabine derivative 12 (Scheme 12): cytarabine (2,4 g, 10 mmol), first intermediate A12 (3.6 g, 10 mmol), PyBOP (5.7 g, 11 mmol) and DMAP (0.12 g, 1 mmol) was dissolved in DMF (10 mL) and stirred at 35 °C for 24 hours. The reaction mixture was poured into water, and the mixture was evaporated. EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Alcohol = 25 VIII) to obtain cytarabine derivative 12 (105.6 mg). LC (UV 254 nm) purity 100%. LC-MS m/z 610 [M + Na] ⁺ (Molecular formula C ₃₁ H ₄₅ N ₃ O ₈ , molecular weight 587 ).

Synthesis of the first intermediate product A13 (Scheme 13): phthalic anhydride (3.0 g, 20 mmol) was mixed with n-hexadecanol (5.4 g, 22 mmol), heated at 80 ° C for 5 hours, cooled, The white solid first intermediate A13 was used directly in the next reaction without further purification. Synthesis of cytarabine derivative 13 (Scheme 13): cytarabine (2,4 g, 10 mmol), first intermediate A13 (3.9 g, 10 mmol), PyBOP (5.7 g, 11 mmol) and DMAP (0.12 g, 1 mmol) was dissolved in DMF (10 mL) and stirred at 35 °C for 24 hours. The reaction solution was poured into water, and extracted with EtOAc EtOAc EtOAc EtOAc. /methanol = 25 VIII), obtained cytarabine derivative 13 (100.6 mg). LC (UV 254 nm) purity 98%. LC-MS m/z 638 [M + Na] ⁺ (Molecular formula C ₃₃ H ₄₉ N ₃ O ₈ , molecular weight 615 ).

Synthesis of the first intermediate product A14 (Scheme 14): phthalic anhydride (3.0 g, 20 mmol) mixed with n-octadecyl alcohol (5.3 g, 20 mmol), heated at 80 ° C for 5 hours, cooled, The white solid first intermediate A14 was used directly in the next step without further purification. Synthesis of cytarabine derivative 14 (Scheme 14): cytarabine (2,4 g, 10 mmol), first intermediate A14 (4.2 g, 10 mmol), PyBOP (5.7 g, 11 mmol), and DMAP (0.12 g, 1 mmol) was dissolved in DMF (10 ml) and stirred at 35 °C for 24 hours. The reaction solution was poured into water, extracted with ethyl acetate three times, and the ethyl acetate solution was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness, and purified by column chromatography (silica gel, developing solvent: dichloromethane) /methanol = 25/1), the cytarabine derivative 14 (117.8 mg) was obtained. LC (UV 254 nm) purity 99%. LC-MS m/z 564 [M + Na] ⁺ (Molecular formula C ₃₅ H ₅₃ N ₃ O ₈ , molecular weight 643 ).

Combined

Synthesis of second intermediate product B15 (Scheme 15): n-decyl alcohol (3.79 g, 24 mmol) dissolved in 50 ml of tetrahydrofuran, then 1,4-cyclohexanedicarboxylic acid (3.44 g, 20 mmol) and p-toluene The acid (Ol g) was heated to reflux for 5 hours. The second intermediate product B15 obtained was used in the next step without further purification.

Synthesis of cytarabine derivative 15 (Scheme 15): cytarabine (1 g, 4.1 mmol), second intermediate B15 (1.4 g, 4.5 mmol), PyBOP ( 2.35 g, 4.5 mmol), and DMAP (0.055 g, 0.45 mmol) Dissolved in DMF (10 ml) and stirred at room temperature for 12 h. The reaction solution is poured into water to precipitate a solid, and the solid is purified by column chromatography (silica gel, developing solvent: dichloro Decane/nonanol = 15/1) gave the cytarabine derivative 15 (75.3 mg). LC (UV 254 nm) purity 97%. LC-MS m/z 538 [M + H] + (Molecular formula C ₂₇ H ₄₃ N ₃ O ₈ , molecular weight 537 ). Synthetic route 16:

First

In 50 ml of dioxane, then 1,4-cyclohexanedicarboxylic acid (3.44 g, 20 mmol) and p-toluenesulfonic acid (0.1 g) were added and heated under reflux for 5 hours. The second intermediate product B16 obtained was used in the next step without further purification.

Synthesis of cytarabine derivative 16 (Scheme 16): cytarabine (1 g, 4.1 mmol), second intermediate B16 (1.53 g, 4.5 mmol), PyBOP (2.35 g, 4.5 mmol) and DMAP ( 0.055 g, 0.45 mmol) was dissolved in DMF (10 ml) and stirred at room temperature for 12 h. The reaction solution was poured into water to precipitate a solid. The solid was purified by column chromatography (silica gel, solvent: methylene chloride / methanol = 15/1) to afford cytidine derivative 16 (27 mg). LC (UV 254 nm) purity 96%. LC-MS m/z 564 [M + H] ⁺ 566 (M. C ₂₉ H ₄₇ N ₃ 0 ₈ , molecular weight 565 ).

Synthetic route 17:

Synthesis of second intermediate product B17 (Scheme 17): n-tetradecyl alcohol (5.1 g, 24 mmol) dissolved in 50 ml of dioxane, then 1,4-cyclohexanedicarboxylic acid (3.44 g, 20 mmol) and The p-toluenesulfonic acid (0.1 g) was refluxed for 5 hours. The obtained second intermediate product was used in the next reaction without further purification.

Synthesis of cytarabine derivative 17 (Scheme 17): cytarabine (lg, 4.1 mmol), second intermediate B17 (1.66 g, 4.5 mmol), PyBOP (2.35 g, 4.5 mmol) and DMAP (0.055) g, 0.45 mmol) Dissolved in DMF (10 ml) and stirred at room temperature for 12 h. The reaction solution was poured into water to precipitate a solid, and the solid was purified by column chromatography (silica gel, developing solvent: dichloromethane / decyl alcohol = 10/1) to obtain cytarabine derivative 17 (71.7 mg). . LC (UV 254 nm) purity 95%. LC-MS m/z 594 [M + H] ⁺ (Molecular formula C ₃₁ H ₅₁ N ₃ O ₈ , molecular weight 593 ). Synthetic route 18:

Synthesis of second intermediate product B18 (Scheme 18): n-hexadecanol (5.8 g, 24 mmol) dissolved in 50 ml of tetrahydrofuran, then 1,4-cyclohexanedicarboxylic acid (3.4 g, 20 mmol) and iridium The benzenesulfonic acid (0.1 g) was heated to reflux for 5 hours. The obtained second intermediate product B18 was used in the next reaction without further purification.

Synthesis of cytarabine derivative 18 (Scheme 18): cytarabine (lg, 4.1 mmol), second intermediate B18 (1.78 g, 4.5 mmol), PyBOP ( 2.35 g, 4.5 mmol) and DMAP (0.055) g, 0.45 mmol) Dissolved in DMF (10 ml) and stirred at room temperature for 12 h. The reaction solution was poured into water to precipitate a solid, and the solid was purified by column chromatography (silica gel, solvent: methylene chloride / decyl alcohol = 15/1) to obtain cytarabine derivative 18 (42.6 mg). LC (UV 254 nm ) The purity is 98%. LC-MS m/z 622 [M + H] + (Molecular formula C ₃₃ H ₅₅ N ₃ O ₈ , molecular weight 621 ).

Synthesis of second intermediate product B19 (Scheme 19): n-Octadecyl alcohol ( 6.48 g, 24 mmol) dissolved in 50 mL of tetrahydrofuran, then 1,4-cyclohexanedicarboxylic acid (3.4 g, 20 mmol) and p-toluene The sulfonic acid (0.1 g) was heated to reflux for 5 hours. The obtained second intermediate product B19 was used in the next reaction without further purification.

Synthesis of cytarabine derivative 19 (Scheme 19): cytarabine (1 g, 4.1 mmol), second intermediate B19 (1.91 g, 4.5 mmol), PyBOP ( 2.35 g, 4.5 mmol) and DMAP ( 0.055 g, 0.45 mmol) was dissolved in DMF (10 ml) and stirred at room temperature for 12 h. The reaction solution was poured into water to precipitate a solid, which was purified by column chromatography (silica gel, toluene: methylene chloride/methanol = 15/1) to afford cytidine derivative 19 ( 27.2 mg). LC (UV 254 nm) purity 97%. LC-MS w/z 650 [M + H] + (Molecular formula C ₃₅ H ₅₉ N ₃ O ₈ , molecular weight 649 ). Synthetic route 20:

HOOC

Synthesis of the third intermediate product C20 (Scheme 20): Toluene dicarboxylic acid (6.6 g, 40 mmol) was added to SOCl ₂ (20 ml), DMF (2 drops) was added, and the reaction was refluxed for 4 hours. The SOCI ₂ was unsold, and the obtained third intermediate C20 was used in the next reaction without further purification.

Synthesis of the fourth intermediate product D20 (Scheme 20): Decantol (3.16 g, 20 mmol) in dioxane (20 ml) followed by Et ₃ N (3 ml), third intermediate C20 (4.06 g) , 20 mmol ) dissolved in dioxane. Decitol was added dropwise to the third intermediate C20 under an ice bath, and the reaction was carried out for 4 hours, and the solvent was evaporated. The obtained fourth intermediate D20 was used in the next step without further purification.

Synthesis of cytarabine derivative 20 (Scheme 20): cytarabine (1.2 g, 5 mmol), fourth intermediate D20 (1.5 g, 5 mmol), PyBOP (2.8 g, 5.5 mmol) and DMAP ( 0.06 g, 0.5 mmol) was dissolved in DMF (10 ml) and stirred at room temperature for 12 h. The reaction solution was purified by column chromatography (silica gel,ield: methylene chloride/decanol=15/1) to afford cytidine derivative 20 (31 mg). LC (UV 254 nm) purity 98%. LC-MS m/z 532 [M + Hf (M. C ₂₇ H ₃₇ N ₃ 0 ₈ , molecular weight 531). Synthetic route 21:

Synthesis of the third intermediate product C21 (Scheme 21): To a solution of terephthalic acid (6.6 g, 40 mmol) in SOCl ₂ (20 ml), DMF (2 drops) was added, and the mixture was heated to reflux for 4 hours. The SOCI ₂ was unsold, and the obtained third intermediate C21 was used in the next reaction without further purification. Synthesis of the fourth intermediate product D21 (Scheme 21): Dodecyl alcohol (3.72 g, 20 mmol) was dissolved in dioxane (30 ml) followed by Et ₃ N (3 ml), third intermediate C21 (4.06) g, 20 mmol) was dissolved in dioxane (20 ml). The decanol was added dropwise to the third intermediate product C21 under an ice bath, and the reaction was carried out for 4 hours, and the solvent was evaporated. The obtained fourth intermediate D21 was used in the next step without further purification.

Synthesis of cytarabine derivative 21 (Scheme 21): cytarabine (1.2 g, 5 mmol), fourth intermediate D21 (1.6 g, 5 mmol), PyBOP (2.8 g, 5.5 mmol) and DMAP ( 0.06 g, 0.5 mmol) dissolved in DMF (10 ml). The reaction mixture was purified by column chromatography (silica gel,ield: methylene chloride/decanol=15/1) to afford cytidine derivative 21 (40.5 mg). LC (UV 254 nm) purity 98%. LC-MS m 560 [M + H] dec. (M. C ₂₉ H ₄₁ N ₃ O ₈ , molecular weight 559 ). Synthetic Route 22: OC H

Synthesis of the third intermediate product C22 (Scheme 22): To a solution of m-benzoic acid (10 g, 60 mmol) in SOCl ₂ (30 ml), DMF (2 drops) was added, and the mixture was heated to reflux for 5 hours. The SOCI ₂ was unsold, and the obtained third intermediate C22 was used in the next reaction without further purification. Synthesis of the fourth intermediate D (Scheme 22): Tetrapropanol (4.2 g, 20 mmol) was dissolved in dioxane (20 ml) followed by Et ₃ N (4 ml), third intermediate C22 (4.04) g, 20 mmol) was dissolved in dioxane (20 ml). The tetradecyl alcohol was added dropwise to the third intermediate product C22 under ice bath, The solvent should be evaporated in 4 h. The obtained fourth intermediate D22 was used in the next reaction without further purification.

Synthesis of cytarabine derivative 22 (Scheme 22): cytarabine (1.2 g, 5 mmol), fourth intermediate D22 (1.9 g, 5 mmol), PyBOP (2.86 g, 5.5 mmol) and DMAP ( 0.061 g, 0.5 mmol) dissolved in DMF (10 ml). The reaction solution was purified by column chromatography (silica gel,ield: methylene chloride/methanol = 10/1) to afford cytidine derivative 22 (34.4 mg). LC (UV 254 nm) purity 98%. LC-MS m/z 588 [M + H] ⁺ (Molecular formula C ₃₁ H ₄₅ N ₃ O ₈ , molecular weight 587 ). Synthetic route 23:

Synthesis of the third intermediate product C23 (Scheme 23): To a solution of sulphuric acid (10 g, 60 mmol) was added to SOCl ₂ (30 ml), DMF (2 drops) was added, and the mixture was heated to reflux for 5 hours. The SOCI ₂ was unsold, and the obtained third intermediate C23 was used in the next reaction without further purification. Synthesis of Compound R (Route 23) ^4: the cetyl alcohol (4.84 g, 20 mmol) was dissolved in dioxane (20 ml) was added Et ₃ N (4 ml), a third intermediate C23 (4.04 g, 20 mmol) was dissolved in dioxane (20 ml). Cetyl alcohol was added dropwise to the third intermediate product C23 under an ice bath, and the reaction was carried out for 4 hours, and the solvent was evaporated. The obtained fourth intermediate D was used in the next reaction without further purification.

Synthesis of cytarabine derivative 23 (Scheme 23): cytarabine (1.2 g, 5 mmol), fourth Intermediate D23 ( 1.95 g, 5 mmol), PyBOP ( 2.86 g, 5.5 mmol) and DMAP (0.06 g, 0.5 mmol) were dissolved in DMF (10 ml) and stirred at room temperature for 12 hours. The reaction solution was purified by column chromatography (silica gel,ield: methylene chloride / decyl alcohol = 10/1) to give cytidine derivative 23 (99 mg). LC (UV 254 nm) purity 97%. LC-MS m/z 616 [M + H] + (M. C ₃₃ H ₄₉ N ₃ O ₈ , molecular weight 615 ). Synthetic route 24:

Synthesis of the third intermediate product C24 (Scheme 24): Isophthalic acid (10 g, 60 mmol) was added to SOCl ₂ (30 ml), DMF (2 drops) was added, and the mixture was heated to reflux for 5 hours. The SOCI ₂ was spun off and the third intermediate C24 obtained was used in the next step without further purification. Synthesis of the fourth intermediate product D24 (Scheme 24): octadecyl alcohol (5.4 g, 20 mmol) in dioxane (20 ml) followed by Et ₃ N (4 ml), third intermediate C24 (4.04) g, 20 mmol) was dissolved in dioxane (20 ml). The octadecyl alcohol was added dropwise to the third intermediate product C24 under an ice bath, and the reaction was carried out for 4 hours, and the solvent was evaporated. The obtained fourth intermediate D24 was used in the next reaction without further purification.

Synthesis of cytarabine derivative 24 (Scheme 24): cytarabine (1.2 g, 5 mmol), fourth intermediate D24 (2.02 g, 5 mmol), PyBOP (2.86 g, 5.5 mmol) and DMAP ( 0.06 g, 0.5 mmol) Dissolved in DMF (10 ml) and stirred at room temperature for 12 h. The reaction mixture was subjected to column chromatography to purify column chromatography (yield: silica gel, solvent: methylene chloride/methanol = 10/1) to obtain cytarabine derivative 24 (38.1 mg). LC (UV 254 nm) purity 96%. LC- MS m/z 644 [M + H]+ (molecular formula C ₃₅ H ₅₃ N ₃ O _s , molecular weight 643 ). Synthetic route 25:

Synthesis of the third intermediate product C25 (Scheme 25): terephthalic acid (6.6 g, 40 mmol) was added to SOCl ₂ (20 ml), DMF (2 drops) was added, and the mixture was heated to reflux for 4 hours. The S0C1 ₂ was spun off and the third intermediate C25 obtained was used in the next step without further purification. Synthesis of the fourth intermediate product D (Route 25): Ten-ol (3.16 g, 20 mmol) was dissolved in dioxane (20 ml) was added Et ₃ N ₍₃ ml), the third intermediate C25 (4.04 g , 20 mmol) was dissolved in dioxane (20 ml). Decitol was added dropwise to the third intermediate C25 under an ice bath, and the reaction was carried out for 4 hours, and the solvent was evaporated. The obtained fourth intermediate D25 was used in the next step without further purification.

Synthesis of cytarabine derivative 25 (Scheme 25): cytarabine (1.2 g, 5 mmol), fourth intermediate D25 (1.5 g, 5 mmol), PyBOP (2.86 g, 5.5 mmol) and DMAP ( 0.06 g, 0.5 mmol) dissolved in DMF (10 ml) and stirred at room temperature for 12 h. The reaction solution was purified by column chromatography (silica gel, solvent: dichloromethane / decyl alcohol = 15/1 to give cytidine derivative 25 (22.5 mg). LC (UV 254 nm) purity 95%. - MS m 々 532 [M + H] dec (molecular formula C ₂₇ H ₃₇ N ₃ O ₈ , molecular weight 531 ).

Synthesis of the third intermediate product C26 (Scheme 26): terephthalic acid (6.6 g, 40 mmol) was added to SOCl ₂ (20 ml), DMF (2 drops) was added, and the mixture was heated to reflux for 4 hours. The SOCI ₂ was spun off and the third intermediate C26 obtained was used in the next step without further purification. D26 of the fourth intermediate product synthesis (Scheme 26): The dodecyl alcohol (3.72 g, 20 mmol) was dissolved in dioxane (20 ml) was added Et ₃ N ₍₃ ml), the third intermediate C26 (4.04 g, 20 mmol) was dissolved in dioxane (20 ml). The dodecanol was added dropwise to the third intermediate product C26 under an ice bath, and reacted for 4 hours, and the solvent was distilled off. The obtained fourth intermediate D26 was used in the next step without further purification.

Synthesis of cytarabine derivative 26 (Scheme 26): cytarabine (1.2 g, 5 mmol), fourth intermediate D26 (1.6 g, 5 mmol), PyBOP (2.86 g, 5.5 mmol) and DMAP ( 0.06 g, 0.5 mmol) dissolved in DMF (10 ml) and stirred at room temperature for 12 h. The reaction mixture was subjected to column chromatography (silica gel, DCM: MeOH = 15:1) to afford cytidine derivative 26 (29.7 mg). LC (UV 254 nm) purity 93%. LC-MS m/z 560 [M + H] ⁺ (M. C ₂₉ H ₄₁ N ₃ O ₈ , molecular weight 559 ). Synthetic route 27:

Synthesis of the third intermediate product C27 (Scheme 27): terephthalic acid (6.6 g, 40 mmol) was added to SOCl ₂ (20 ml), DMF (2 drops) was added, and the mixture was heated to reflux for 4 hours. The SOCI ₂ was spun off and the third intermediate C27 obtained was used in the next step without further purification. Synthesis of the fourth intermediate product D27 (Scheme 27): Tetrapropanol (4.2 g, 20 mmol) was dissolved in dioxane (20 ml) followed by Et ₃ N (3 ml), third intermediate C27 (4.04) g, 20 mmol) was dissolved in dioxane (20 ml). Tetrapropanol was added dropwise to the third intermediate product C27 under ice-cooling for 4 hours, and the solvent was evaporated. The obtained intermediate product D27 was directly used for the next reaction without further purification.

Synthesis of cytarabine derivative 27 (Scheme 27): cytarabine (1.2 g, 5 mmol), fourth intermediate D27 (1.8 g, 5 mmol), PyBOP (2.86 g, 5.5 mmol) and DMAP ( 0.06 g, 0.5 mmol) dissolved in DMF (10 ml) and stirred at room temperature for 12 h. The reaction mixture was subjected to column chromatography (yield: silica gel, toluene: methylene chloride / decyl alcohol = 15/1) to afford cytidine derivative 27 (26 mg). LC (UV 254 nm) purity 99%. LC-MS m/z 588 [M + H] ⁺ (M. C ₃₁ H ₄₅ N ₃ O ₈ , molecular weight 587 ). Synthetic route 28:

Synthesis of the third intermediate product C28 (Scheme 28): terephthalic acid (6.6 g, 40 mmol) was added to SOCl ₂ (20 ml), DMF (2 drops) was added, and the mixture was heated to reflux for 4 hours. The SOCI ₂ was spun off and the third intermediate C28 obtained was used in the next step without further purification. Synthesis of the fourth intermediate product D28 (Scheme 28): Cetyl alcohol (4.8 g, 20 mmol) was dissolved in dioxane (20 ml) followed by Et ₃ N (3 ml), third intermediate C28 (4.04) g, 20 mmol) was dissolved in dioxane (20 ml). Cetyl alcohol was added dropwise to a third intermediate product C28 under a water bath, and reacted for 4 hours, and the solvent was distilled off. The obtained fourth intermediate D28 was used in the next step without further purification.

Synthesis of cytarabine derivative 28 (Scheme 28): cytarabine (1.2 g, 5 mmol), fourth intermediate D28 (2.0 g, 5 mmol), PyBOP (2.86 g, 5.5 mmol) and DMAP ( 0.06 g, 0.5 mmol) dissolved in DMF (10 ml) and stirred at room temperature for 12 h. The reaction mixture was subjected to column chromatography (yield: silica gel, solvent: methylene chloride/methanol = 15/1) to afford cytidine derivative 28 (26.6 mg). LC (UV 254 nm) purity 99%. LC-MS m/z 616 [M + H] + (M. C ₃₃ H ₄₉ N ₃ O ₈ , molecular weight 615 ). Synthetic route 29:

Synthesis of the third intermediate product C29 (Scheme 29): terephthalic acid (6.6 g, 40 mmol) was added to SOCl ₂ (20 ml), DMF (2 drops) was added, and the mixture was heated to reflux for 4 hours. The SOCI ₂ was spun off and the third intermediate C29 obtained was used in the next step without further purification. Synthesis of a fourth intermediate D29 (Route 29): The stearyl alcohol (5.4 g, 20 mmol) was dissolved in dioxane (20 ml) was added Et ₃ N ₍₃ ml), the third intermediate C29 (4.04 g, 20 mmol) was dissolved in dioxane (20 ml). The octadecyl alcohol was added dropwise to the third intermediate product C29 under an ice bath, and the reaction was carried out for 4 hours, and the solvent was evaporated. The obtained fourth intermediate D29 was used in the next step without further purification.

Synthesis of cytarabine derivative 29 (Scheme 29): cytarabine (1.2 g, 5 mmol), fourth intermediate D29 (2.1 g, 5 mmol), PyBOP (2.86 g, 5.5 mmol) and DMAP ( 0.06 g, 0.5 mmol) dissolved in DMF (10 ml) and stirred at room temperature for 12 h. The reaction mixture was subjected to column chromatography (yield: silica gel, toluene: methylene chloride / decyl alcohol = 15/1) to give the cytidine derivative 29 (37.9 mg). LC (UV 254 nm) purity 97%. LC-MS m/z 644 [M + H] dec. (Molecular formula C ₃₅ H ₅₃ N ₃ 0 ₈ , molecular weight 643 ). Synthetic route 30:

Synthesis of the fifth intermediate product E30 (Scheme 30): POCl ₃ (3.0 g, 20 mmol) was dissolved in triethyl phosphate (25 ml), and cytarabine (4.9 g, 20 mmol) was added at 0 °C. After reacting for 1 h, the reaction mixture was washed with diethyl ether to give a fifth intermediate product E30.

Synthesis of cytarabine derivative 30 (Scheme 30): The fifth intermediate product E30 (0.5 g, 1.4 mmol) was added to decyl alcohol (20 ml), stirred at 60 ° C for 4 h, and diluted with hydrochloric acid to adjust the pH to 7, spin dry sterol, PTLC (developing agent: isopropanol / ammonia = 10/1), to obtain cytarabine derivative 30 (9.3 mg). The purity of LC (UV 254 nm) was 99%. LC-MS m/z 352 [M + H] + (M.s. C _u H ₁₈ N ₃ O ₈ P, molecular weight 351 ). Synthetic route 31:

Synthesis of the fifth intermediate product E31 (Scheme 31): POCl ₃ (1.25 g, 8.2 mmol) was dissolved in triethyl phosphate (10 ml), and cytarabine (1 g, 4.1 mmol) was added at 0 °C. After 1 h, the reaction mixture was washed with diethyl ether to give a fifth intermediate product E31.

Synthesis of cytarabine derivative 31 (Scheme 31): The fifth intermediate product E31 (0.5 g, 1.4 mmol) was added to absolute ethanol (20 ml), stirred at 60 ° C for 4 h, and diluted with hydrochloric acid to adjust the pH to 7, spin dry ethanol, PTLC (developing agent: isopropanol / ammonia = 2 / 1), get cytarabine derivative 31 ( 87.1 Mg). LC (UV 254 nm) purity 98%. LC-MS m/z 380 [M + H] + (Molecular formula C ₁₃ H ₂₂ N ₃ O ₈ P, molecular weight 379 ). Synthetic route 32:

Synthesis of the fifth intermediate product E32 (Scheme 32): POCl ₃ (1.25 g, 8.2 mmol) was dissolved in triethyl phosphate (10 ml), and cytarabine (1 g, 4.1 mmol) was added at 0 ° C. After 1 h, the reaction mixture was washed with diethyl ether to give a fifth intermediate product E32.

Synthesis of cytarabine derivative 32 (Scheme 32): The fifth intermediate product E32 (0.5 g, 1.4 mmol) was added to n-butanol (20 ml), stirred at 60 ° C for 4 h, and diluted with hydrochloric acid to adjust pH. To 7, spin dry n-butanol, PTLC (developing agent: isopropanol / ammonia = 2 / 1), to obtain cytarabine derivative 32 (20.4 mg). LC (UV 254 nm) purity 95%. LC-MS m/z 436 [M + H] dec. (M. C ₁₇ H ₃₀ N ₃ O ₈ P, molecular weight 435 ). Synthetic route 33:

E33

Synthesis of the fifth intermediate product E33 (Scheme 33): POCl ₃ (1.25 g, 8.2 mmol) was dissolved in triethyl phosphate (10 ml), and cytarabine (1 g, 4.1 mmol) was added at 0 °C. 1 h, The reaction mixture was washed with diethyl ether to give a fifth intermediate product E33.

Synthesis of cytarabine derivative 33 (Scheme 33): Fifth intermediate E33 (0.9 g, 2.5 mmol) and n-octanol (0.65 g, 5 mmol) dissolved in triethyl phosphate (5 ml), 80 Stir at °C for 5 h, dilute hydrochloric acid to adjust the pH to 7, and wash the mixture with diethyl ether. Solid PTLC (developing solvent: isopropanol/ammonia = 1/1) to obtain cytarabine derivative 33 (1.8 mg) ). LC (UV 254 nm) purity 95%.

LC-MS m/z 570 [M + Na] ⁺ (Molecular formula C ₂₅ H ₄₆ N ₃ O ₈ P, molecular weight 547 ). Synthetic drug tumor cytotoxicity test protocol

Inhibition of tumor cells by the cytarabine derivative of the invention and preparation thereof

Test material

1) Cell line:

The HL-60 cell line was suspended and grown in a medium containing 10% fetal bovine serum (Hyclone 々 RPMI 1640 cell culture medium, and the conventional cell culture was maintained at an initial cell concentration of about 3*10 ⁵ /ml, and passaged 1:3 once every three days. Passage (5* 10 ⁵ /ml) one day before the experiment, the cell concentration during the experiment is between 7.5~10*10 ⁵ /ml.

BEL-7402 cell line and HT-29 cell line were adherently grown and cultured in D-MEM cell culture medium of 10% fetal bovine serum (Hyclone). The initial cell concentration in conventional culture was about 3*10 ⁵ /ml, 2 ~3 days 1: 3 pass once. Passage 1:2 on the day before the experiment, the cell concentration during the experiment was between 5~10*10 ⁵ /ml.

2) Dissolution and dilution of the drug: According to the weight and molecular weight of the cytarabine derivative provided, first add DMSO 100~200 μΐ, then add physiological saline (NS), so that the concentration of the drug obtained after dilution is 5 mM. The final concentration of DMSO does not exceed 10%).

3) D-MEM or RPMI 1640 Cell Culture Medium, Gibco

4) Fetal bovine serum, Hyclone

5) Cell digestive juice, 0.25 ◦ /. Trypsin + 0.02 % EDTA

6) PBS phosphate buffer MTT solution, MTT dry powder (Sigma), fully dissolved in PBS to prepare 5 mg / ml, 0 · 22 μιη microporous membrane filtration, and then stored at -20 °C.

10% acidified SDS, 0.01NHC1

Centrifuge tubes, straws, etc. (BD company), 96-well plate (Costar)

Step:

Cell inoculation: Cells grown 24 hours after passage, in good growth. The cells were routinely harvested, and the cell concentration was adjusted to 2 x ^{10 5} /ml (adherent cells) ~ ³ x ^{10 5} /ml (suspended cells) with fresh medium. The adherent cells were inoculated at 100 μΐ/well, cultured in a 37 ° C, 5% CO ₂ incubator for 24 h, and the old culture solution was discarded, and fresh culture medium was added at 95 μM/well. Suspension cells were inoculated directly to 95 μΐ/well.

Drug treatment: There are 6 concentration gradients for each drug, 3 duplicate wells for each concentration, and 5 duplicate wells for the drug blank control group. Ara-C control was performed at the same time for each test. The concentration of HT-29 and BEL-7402 fines was 5, 2.5, 1.25, 0.625, 0.3125, 0.16 mM, 5 μl per well, and the final concentrations were 0.25, 0.125, 0.0625, 0.03125, 0.016, 0.008 mM. 5 % ΐ normal saline was added to the control group; the concentration of HL-60 cells added to the drug was

5χ10 ^-3 , 2.5χ10 ^-3 , 1.25χ10 ^-3 , 0·625χ10 ^-3 , 0·3125χ10 ^-3 , Ο.ΙόχΙΟ" ³ mM, the corresponding final concentration is 2.5χ1θΛ 1.25χ10 ^-4 , 6.25χ10 ^-5 , ^{^{^{3.125χ10 -5, 1.6χ10 -5, 8x10- 6}}} mM, was added 5 μΐ saline control group.

Cell culture and testing: After adding the drug, 37 . C, incubated in 5% CO ₂ incubator for 72 h, then add MTT 10 μΐ per well, continue to culture for 4 h, add 100 μΐ 10% SDS per well (including 0.01N)

HCl) was dissolved. After 24 h, the absorbance (A) of each well was measured with a Bio-rad Model 680 ELISA reader with a detection wavelength of 570 nm and a reference wavelength of 630 nm.

Calculation: First, average the absorbance of each well (remove the data from over-disparity), calculate the inhibition rate (IR) for each drug concentration of each cell, I (%) = (1 - A Ao) X 100%, A _n is the average absorbance of the experimental well, A. The mean absorbance of the drug blank control wells. Using the EXCEL software, plot the drug concentration effect curve and select a reasonable calculation method to calculate 50% cell survival. Drug concentration (IC ₅₀ ).

Figure 4 is a graph showing the representative drug concentration-inhibition rate of cytosine derivatives inhibiting BEL-7402 liver cancer cell lines. Among them, JF001, JF017, JF019, JF029 and JF033 are cytarabine derivatives synthesized according to the synthetic routes 1, 17, 19, 29, and 33, respectively. Arac is the English abbreviation for cytarabine.

Tables 1-4 list representative cytarabine derivatives to inhibit the biological activity of different tumor cells. JF004, JF005, JF006, JF007, JF009, JF013, JF020 and JF033 are cytarabine derivatives synthesized according to synthetic routes 4, 5, 6, 7, 9, 13, 20 and 33, respectively. Table 1

Table 2

/010ZN3/X3d Table 4

The above test results indicate that the cytarabine derivative of the present invention inhibits tumor cells

Claims

Claim

A cytarabine derivative characterized in that the cytarabine derivative is a compound having the following general formula (I):

(I)

Wherein, when X = OH, W represents any one of c = o, s (o) o and c (o) o; Z is an alkyl group or any of the following representative groups:

Wherein, m = 0, 1, 2; n = 1, 2, 3; the n-indicated group contained in the parenthesis may be substituted for the benzene ring, the aromatic ring, the naphthalene ring, the carbocyclic ring, the heterocyclic ring Any position of the ortho-, m-, or ~- of the structural unit or any one of 1 i -, 3- or any of α - and β - f or a combination of these positions;

Wherein R ¹ R ² is a (^ _-18 saturated or unsaturated aliphatic group, the unsaturated aliphatic group containing at least one unsaturated bond, the unsaturated bond comprising a cis or trans isomer ;

Wherein R ³ is an alkyl group selected from the group consisting of H, OH, OCOR, ester group COOR, dC ₁₈ , and C _3-18 cycloalkyl group. Alkenyl group, alkynyl group of C ₂ _ ₁₍₎ , trifluoromethyl group, benzyl group, aryl group, halogen atom group, Acyl COR', carbonyl COR, cyano, amino, substituted amino, nitro, xanyl, amide, CONR, ₂ and NHCOR', xanthyl, amino, carbocyclyl, heterocyclyl, alkoxy Any one of the alkylthio groups SR, wherein R is RR ² as defined above;

Where X ≠OH, X represents O-Pt XOR ¹ ) or phosphate group or

Wherein A represents any of O, S and CH ₂ , p = l-5, and the phosphate group includes a monophosphate group, a diphosphate group and a triphosphate group,

W-Z- represents a hydrogen atom or W, and Z represents a group as defined above, respectively.

The cytarabine derivative according to claim 1, wherein: R ¹ , R ² AH, C _1-18 alkyl, C _3-18 cycloalkyl, C ₂ -i8 Alkenyl, c _2-18 alkynyl, c _3-1 . Any one of a cycloalkenyl group, a benzyl group, a phenyl group, an aromatic ring group, a carbocyclic group, and a heterocyclic group.

The cytarabine derivative according to claim 1 or 2, wherein the cytarabine derivative is a cytarabine derivative when X = OH in the formula (I).

The cytarabine derivative according to claim 1 or 2, wherein the cytarabine derivative is a cytarabine derivative when W-Z of the formula (I) is H.

The cytarabine derivative according to claim 1 or 2, wherein the structural formula of the cytarabine derivative is any one of the following structural formulae:

46

n = 2-8

a synthetic route for cytarabine derivatives, characterized in that: cytarabine and acetic anhydride are dissolved In the decyl alcohol, the reaction mixture was heated under reflux for 4 hours, and the obtained reaction liquid was purified by column chromatography to give the cytosine derivative of the formula (I).

7. A synthetic route of cytarabine derivatives, characterized in that: cytarabine, acetylsalicylic acid or o-decyloxybenzoic acid, PyBOP and DMAP are dissolved in DMF, stirred at room temperature for 12 hours to obtain a reaction solution, The reaction liquid is purified by column chromatography or the reaction liquid is suspended with water, washed with ethyl acetate, and the aqueous layer is allowed to stand to precipitate crystals, which are filtered and dried to obtain a cytarabine derivative of the formula (I).

8. The synthetic route of cytarabine derivatives, including the following steps:

(1) The acid anhydride compound is mixed with a fatty alcohol, heated and melted, reacted for 4 to 5 hours, and cooled to obtain a first intermediate product (A) which is directly used in the next reaction without further purification;

(2) Dissolving cytarabine, first intermediate product (A), PyBOP and DMAP in DMF, stirring at 25~50 °C for 12-24 hours to obtain a reaction solution.

The reaction solution is purified by column chromatography or the reaction solution is poured into water to precipitate a solid, and the obtained solid is purified by column chromatography.

Alternatively, the obtained reaction solution was poured into water, and extracted with ethyl acetate three times. The ethyl acetate solution was dried over anhydrous sodium sulfate and filtered, and the filtrate was evaporated to dryness to give a cytidine derivative of the formula (I).

The synthetic route of the cytarabine derivative according to claim 8, wherein the acid anhydride compound is an phthalic acid or a dianhydride compound; the fatty alcohol is decyl alcohol or n-butanol. Any one of lauryl alcohol, n-tetradecyl alcohol, n-hexadecanol, and n-octadecanol.

10. The synthetic route of cytarabine derivatives, including the following steps:

(1) The fatty alcohol is dissolved in tetrahydrofuran or dioxane, and then 1,4-cyclohexanedicarboxylic acid and p-toluenesulfonic acid are added, and the mixture is heated under reflux for 5 hours to obtain a second intermediate product (B) which is obtained without further purification. Used directly in the next reaction;

(2) Dissolving cytarabine, second intermediate product (B), PyBOP and DMAP in DMF, stirring at room temperature for 12 hours, pouring the reaction solution into water, precipitating the solid, and purifying the solid by column chromatography. A cytarabine derivative of the formula (I).

The synthetic route of the cytarabine derivative according to claim 10, wherein the fatty alcohol is any one of n-decyl alcohol, lauryl alcohol, n-tetradecyl alcohol, n-hexadecanol and n-octadecyl alcohol. One.

12. The synthetic route of cytarabine derivatives, including the following steps:

(1) Adding isophthalic acid or phthalic acid to SOCl ₂ , adding 1 to 4 drops of DMF, heating under reflux, reacting for 4 hours, and spinning off SOCl ₂ to obtain a third intermediate product (C). After further purification, it is directly used in the next reaction;

(2) dissolving the fatty alcohol in dioxane and then adding Et ₃ N, the third intermediate product (C) is dissolved in dioxane, and the fatty alcohol is added dropwise to the third intermediate product (C) in an ice bath. , the reaction was carried out for 4 hours, and the solvent was distilled off to obtain a fourth intermediate product (D);

(3) Dissolving cytarabine, fourth intermediate product (D), PyBOP and DMAP in DMF, stirring at room temperature for 12 hours, and separating and purifying the reaction liquid to obtain cytarabine of general formula (I). derivative.

The synthetic route of the cytarabine derivative according to claim 12, wherein the fatty alcohol is any of n-decyl alcohol, lauryl alcohol, n-tetradecyl alcohol, n-hexadecanol and n-octadecyl alcohol. One.

14. A synthetic route for cytarabine derivatives, comprising the following steps:

(1) POCl _{3 is} dissolved in triethyl phosphate, and cytarabine is added at 0 ° C for 1 h. The reaction mixture is washed with diethyl ether to obtain a fifth intermediate product (E), which is directly used without further purification. Next reaction;

(2) The fifth intermediate product (E) is added to the fatty alcohol, stirred at 60 to 80 ° C for 4 to 5 h, and diluted with hydrochloric acid to adjust the pH to 7, and the aliphatic alcohol is spun to obtain the general formula (I). Cytosine derivatives.

The synthetic route of the cytarabine derivative according to claim 14, wherein the fatty alcohol is any one of methanol, absolute ethanol, n-butanol and n-octanol.

16. A method for preparing a cytarabine derivative preparation, comprising the steps of:

(1) The cytarabine derivative of the formula (I) is dissolved in water, physiological saline, a cyclodextrin aqueous solution, a preparation solution prepared by combining a solvent of any one or more of a water-soluble organic solvent, a nonionic surfactant, a water-soluble lipid, a fatty acid, a fatty acid ester, and a phospholipid;

(2) The preparation solution is further diluted with physiological saline or glucose injection to prepare a cytarabine derivative preparation.

17. A method of preparing a cytarabine derivative preparation according to claim 16, wherein: said organic solvent is ethanol, propylene glycol, glycerin, glyceride, polyethylene glycol, N, N-dioxene A combination solvent of any one or more of a quinone amide and dimethyl sulfoxide.

A cytarabine derivative preparation, which comprises the preparation of the preparation method of the cytarabine derivative preparation of claim 16.

The use of the cytarabine derivative of claim 1 for anticancer and antitumor.

The use of the cytarabine derivative according to claim 19 for anticancer and antitumor, characterized in that the cancer comprises leukemia, solid tumor, lung cancer, colon cancer, liver cancer, central nervous system tumor, ovarian cancer and renal cancer .

21. Use of a cytarabine derivative preparation according to claim 18 for anti-cancer and anti-tumor.

The use of the cytarabine derivative preparation according to claim 21 for anticancer and antitumor, characterized in that the cancer comprises leukemia, solid tumor, lung cancer, colon cancer, liver cancer, central nervous system tumor, ovarian cancer and kidney cancer.

The use of the cytarabine derivative preparation of claim 21 for anticancer and antitumor, characterized in that: the cytarabine derivative preparation is administered in combination with other chemotherapeutic drugs, and the other chemotherapeutic drugs include alkylation Agents, plant alkaloids, antibacterial and anti-tumor sulfonamides, platinum drugs, anti-metabolites and other known anti-cancer drugs.

The use of the cytarabine derivative preparation according to claim 23 for anticancer and antitumor, characterized in that, in the course of the combination, the use of at least one cytarabine having the structural formula of claim 5 "Biology.